Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain

Strope, Jonathan D.; Peer, Cody J.; Sissung, Tristan M.; Hall, O. Morgan; Huang, Phoebe; Harris, Emily M.; Gustafson, Kirk R.; Henrich, Curtis J.; Sigano, Dina M.; Pauly, Gary T.; Bates, Susan E.; Figg, William D.

doi:10.1080/15384047.2019.1683324

Cited by 11 publications

(4 citation statements)

References 55 publications

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“…In this work, we have shown that ABCG2 plays an important role in the passage of meloxicam through BBB and its accumulation in the central nervous system. Several studies have demonstrated the limiting role of ABCG2 in the brain penetration of many drugs [49,50] and how transporter inhibition [51,52] or reduced expression due to genetic variants [24] can improve drug therapies related to the central nervous system. We therefore hypothesized that inhibition of ABCG2 could increase brain accumulation of meloxicam, and consequently, improve the potential treatment or prevention of neurodegenerative diseases with this drug.…”

Section: Discussionmentioning

confidence: 99%

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

García-Lino

Blanco-Paniagua

Astorga-Simon

et al. 2020

Biochemical Pharmacology

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ATP-binding cassette (ABCG2) is an efflux transporter that extrudes xenotoxins from cells in liver, intestine, mammary gland, brain and other organs, affecting the pharmacokinetics, brain accumulation and secretion into milk of several compounds, including antitumoral, antimicrobial and anti-inflammatory drugs. The aim of this study was to investigate whether the widely used anti-inflammatory drug meloxicam is an Abcg2 sustrate, and how this transporter affects its systemic distribution. Using polarized ABCG2-transduced cell lines, we found that meloxicam is efficiently transported by murine Abcg2 and human ABCG2. After oral administration of meloxicam, the area under the plasma concentration-time curve in Abcg2-/mice was 2-fold higher than in wild type mice (146.06 ± 10.57 µg•h/ml versus 73.80 ± 10.00 µg•h/ml). Differences in meloxicam distribution were reported for several tissues, with a 20-fold higher concentration in the brain of Abcg2-/compared to wild-type mice. Meloxicam secretion into milk was also affected by the transporter, with a 2.5-fold higher milk-to-plasma ratio in wild-type compared with Abcg2-/lactating female mice (0.58 ± 0.08 versus 0.23 ± 0.06). We conclude that Abcg2 is an important determinant of the plasma and brain distribution of meloxicam and is clearly involved in its secretion into milk.

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Section: Discussionmentioning

confidence: 99%

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

García-Lino

Blanco-Paniagua

Astorga-Simon

et al. 2020

Biochemical Pharmacology

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“…A study by Strope, et al in 2019 investigated a more specific ABCG2 inhibitor, botryllamide G, and found that it could significantly increase brain concentrations of lapatinib. However, ABCB1 would also need to be blocked for a complete efflux transporter inhibition 112 . In addition, off-target effects of Pgp inhibition are a significant pitfall since ABCB1 and ABCG2 are expressed in the gut, liver, and kidney.…”

Section: Blood-brain Barrier Modulationmentioning

confidence: 99%

Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy

Upton¹,

Ung²,

George³

et al. 2022

Theranostics

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Despite significant advances in research, the prognosis for both primary and secondary brain cancers remains poor. The blood-brain barrier (BBB) is a complex and unique semi-permeable membrane that serves as a protective structure to maintain homeostasis within the brain. However, it presents a significant challenge for the delivery of therapeutics into the brain and tumor. Some brain tumors are known to compromise BBB integrity, producing a highly heterogeneous vasculature known as the blood-tumor-barrier (BTB). Identifying strategies to bypass these obstacles to improve the penetrability of anticancer therapeutics has been the focus of research in this area. In this review, we discuss the strategies that have been investigated to evade or alter the cellular and molecular barriers of both the BBB and the BTB and detail the methods currently under preclinical or clinical investigation, including molecular, biological, and physical processes to overcome the BBB or BTB. Increased understanding of the BBB and BTB and the current methods of overcoming these barriers will enable the development of new and more effective treatment strategies for brain tumors.

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“…Recently, ABCG2 has received increasing attention due to its mutable pharmacological binding sites (10). Evidence suggested that the upregulation of the ABCG2 gene may be…”

Section: Introductionmentioning

confidence: 99%

“…Recently, ABCG2 has received increasing attention due to its mutable pharmacological binding sites ( 10 ). Evidence suggested that the upregulation of the ABCG2 gene may be closely associated with the high recurrence rate and adverse therapeutic response of hematological malignancies ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

KD025, an anti‑adipocyte differentiation drug, enhances the efficacy of conventional chemotherapeutic drugs in ABCG2‑overexpressing leukemia cells

et al. 2020

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Most patients with advanced leukemia eventually die from multidrug resistance (MDR). Chemotherapy-resistant leukemia cells may lead to treatment failure and disease relapse. Overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) leads to MDR, which serves as a potential biomarker and target of therapeutic intervention for leukemia cells. Targeting ABCG2 is a potential strategy for selective therapy and eradicate MDR cells, thus improving malignant leukemia treatment. KD025 (SLx-2119) is a novel Rho-associated protein kinase 2-selective inhibitor, which has been shown to inhibit adipogenesis in human adipose-derived stem cells and restore impaired immune homeostasis in autoimmunity therapy. The present study demonstrated that KD025 improved the efficacy of antineoplastic drugs in ABCG2-overexpressing leukemia cells and primary leukemia blast cells derived from patients with leukemia. Moreover, KD025 significantly inhibited the efflux of [ 3 H]-mitoxantrone and hence accumulated higher levels of [ 3 H]-mitoxantrone in HL60/ABCG2 cells. However, mechanistic research indicated that KD025 did not alter the protein levels and subcellular locations of ABCG2. KD025 may restrain the efflux activity of ABCG2 by obstructing ATPase activity. Taken together, KD025 can sensitize conventional antineoplastic drugs in ABCG2-overexpressing leukemia cells by blocking the pump function of ABCG2 protein. The present findings may provide a novel and useful combinational therapeutic strategy of KD025 and antineoplastic drugs for leukemia patients with ABCG2-mediated MDR.

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Botryllamide G is an ABCG2 inhibitor that improves lapatinib delivery in mouse brain

Cited by 11 publications

References 55 publications

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

Abcg2 transporter affects plasma, milk and tissue levels of meloxicam

Challenges and opportunities to penetrate the blood-brain barrier for brain cancer therapy

KD025, an anti‑adipocyte differentiation drug, enhances the efficacy of conventional chemotherapeutic drugs in ABCG2‑overexpressing leukemia cells

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